Mechanisms of host:parasite immune regulation during Schistosoma mansoni infection

血吸虫病是一种广泛存在的、使人极度衰弱的寄生虫病，影响到亚热带地区较贫穷国家的2.2亿多人，估计每年造成20万人死亡。尽管它很重要，但没有疫苗可用。血吸虫在接触受感染的水后进入人体，并在血液中定居，在那里它们不断暴露于宿主的免疫系统。为了生存，它们已经发展出复杂的免疫逃逸机制，多年来保护它们免受宿主免疫系统的攻击。然而，寄生虫用来抑制免疫的蛋白质的身份仍然未知。对动物模型和生活在血吸虫病流行地区的患者的研究表明，随着时间的推移，有可能建立起对该疾病的保护性免疫；然而，宿主免疫系统所针对的赋予这种保护作用的寄生虫蛋白尚未被发现。本研究项目的主要目标是鉴定宿主抗体靶向的寄生虫蛋白，以保护宿主免受感染，以及寄生虫用来破坏宿主免疫反应的蛋白质。存在于寄生虫外表面或由寄生虫分泌到宿主血液中的蛋白质被认为是这两种功能的主要参与者，因为它们可以直接接触到宿主抗体并可以直接与其免疫细胞相互作用。利用最近在实验室生产的一百多种重组蛋白的大量收集，这些重组蛋白概括了在曼氏血吸虫寄生虫表面自然发现或由其分泌的蛋白质的形状和功能，我们将进行血清学和生化研究。我们将使用对曼氏链球菌感染具有抗性的小鼠和巴西个体的血清，并将其暴露于重组寄生虫蛋白中，以确定与长期感染曼氏链球菌的个体相比，这些具有抗性的个体是否产生针对特定寄生虫蛋白的抗体。我们还将使用一些生化技术来确定哪些寄生虫蛋白能够与人类免疫细胞结合，以及它们如何干扰调节寄生虫感染免疫反应的蛋白质的功能。通过鉴定宿主免疫系统在自然抵抗感染的背景下靶向的寄生虫蛋白和那些在免疫调节中发挥作用的蛋白，我们希望揭示新的候选蛋白，可以开发成急需的血吸虫病疫苗靶点，以对抗这种广泛和高发病率的寄生虫疾病。

Schistosomiasis is a widespread and highly debilitating parasitic disease affecting over 220 million people in the poorer countries of the sub-tropical areas and causing the death of an estimated 200,000 individuals every year. Despite its importance, no vaccine is available. Schistosoma parasites enter the human body after contact with infected water and take residency in the bloodstream, where they are constantly exposed to the host immune system. To survive, they have developed sophisticated mechanisms of immune escape that protects them from the host immune system for many years. However, the identity of the proteins used by the parasite to suppress immunity remains unknown. Study of animal models and of patients living in areas where schistosomiasis is endemic suggests that it is possible to build up a protective immunity to the disease over time; however, the parasite proteins that the host immune system targets to confer this protection have not yet been found. The main goal of this research project is to identify the parasite proteins targeted by host antibodies to confer protection from infection as well as the proteins that the parasite uses to subvert its host's immune response. Proteins present on the outer surface of the parasite or secreted by the parasite into its host's bloodstream are believed to be the main actors of both of these functions as they are directly accessible to the host antibodies and can directly interact with its immune cells. Using a large and recent collection of over one hundred recombinant proteins produced in the laboratory, which recapitulate the shape and function of the proteins naturally found at the surface of or secreted by the Schistosoma mansoni parasite, we will perform serological and biochemical studies. We will use sera from both mice and Brazilian individuals who are resistant to S. mansoni infection and expose them to the recombinant parasite proteins to determine whether these resistant individuals produce antibodies against specific parasite proteins compared to individuals who are chronically infected with S. mansoni. We will also use some biochemical techniques to identify which parasite proteins are able to bind to human immune cells and how they interfere with the function of proteins that regulate the immune response to parasite infection. By identifying the parasite proteins targeted by the host immune system in the context of natural resistance to infection and those that play a role in immunoregulation, we hope to reveal new candidates that can be developed into much-needed schistosomiasis vaccine targets against this widespread and highly-morbid parasitic disease.